Analgesia can be produced by opioid agonists microinjected intraventricularly (supra-spinal) or intrathecally (spinal). Thus both spinal and supraspinal brain sites contain opioid sensitive structures mediating analgesia. Recent studies indicate that morphine and other opioids produce analgesia in part through an indirect mechanism involving the activation of an intrinsic descending pain inhibitory system. My preliminary studies in rats showed that intrathecal naloxone antagonized completely the analgesia produced by intraventricular Beta-endorphin but not that by morphine. Intraventricularly, Beta-endorphin, but nor morphine releases immunoreactive (i.r.) met-enkephalin from the spinal cord while intraventricular morphine but not Beta-endorphin releases i.r. dynorphin 1-8. This evidence supports the hypothesis that Beta-endorphin and morphine elicit the analgesic action via the activation of different neuronal mechanisms. A model working hypothesis for the action of Beta-endorphin and morphine is proposed. The hypothesis is that the descending inhibitory systems can be divided into two systems: an epsilon-opioid receptor mediated descending system and a mu-opioid receptor mediated descending system. The first system is activated by supraspinal Beta-endorphin and is mediated by a spinal enkephalinergic system. The second system is activated by supraspinal morphine and other mu-receptor agonists and is mediated by a spinal dynorphinergic system. The proposed studies are aimed to obtain more evidence to verify this hypothesis by studying the spinal release of endorphins by intraventricular Beta-endorphin, morphine and other opiates in male albino rabbits, cats and male Sprague-Dawley rats. The release of endorphins (met-enkephalin, dynorphin 1-8, and other endorphins) and serotonin and norepinephrine from the spinal cord by intraventricular Beta-endorphin, morphine and other opioid agonists will be studied. A spinal intrathecal superfusion technique will be used to study the spinal release of endophins and biogenic amines. The endorphins in the superfusate will be assayed by radioimmunoassay and also analyzed by HPLC. The serotonin and norepinephrine will be separated by HPLC and quantified with electrochemical detection. Chronic exposure of opioids on the development of the tolerance on the spinal release of i.r. met-endephalin and dynorphin 1-8 by Beta-endorpin and morphine respectively will also be studied. The proposed studies will provide evidence of a physiological role as neurotransmitter for spinal enkephalin and dynorphin and their association with descending analgesic systems.